Madrigal says NASH drug also works in genetic cholesterol disorder

Madrigal Pharma is celebrating after its lead drug, MGL-3196, hit the mark in a phase 2 trial in the second of its two target indications: heterozygous familial hypercholesterolemia (HeFH).

The biotech—which has already seen its share price triple in the last three months mainly on the promise of MGL-3196 in lead indication nonalcoholic steatohepatitis (NASH)—was up another three points to almost $146 in after-hours trading on the Nasdaq as news of the latest data filtered through.

MGL-3196 is billed as a first-in-class liver-directed thyroid hormone receptor beta-selective agonist originally developed by Roche and, while NASH is certainly the bigger opportunity, hitting the mark in HeFH could help unlock another underserved market for the once-daily pill.

In the latest trial, giving Madrigal’s drug on top of a high-dose statin achieved a statistically significant reduction in LDL cholesterol compared to placebo after 12 weeks’ treatment, along with improvements in other biomarkers such as triglyceride levels, apolipoprotein B and lipoprotein(a).

The trial enrolled 116 European patients with HeFH who were not meeting their treatment targets despite current treatment, with 75% of patients on high-dose statins and two-thirds also taking Merck & Co.’s Zetia (ezetimibe). Madrigal’s drug achieved 18.8% LDL cholesterol lowering compared to placebo, with patients on the optimal dose of the drug seeing a 21% reduction.

For the group of patients unable to tolerate high-dose statins, the difference between MGL-3196 and placebo was even bigger at almost 29%.

Similar patterns were seen with triglycerides, ApoB and Lp(a), and Madrigal’s head of R&D, Becky Taub, M.D., described this profile as “unique” for a single drug intended to treat dyslipidemia.

Madrigal CEO Paul Friedman, M.D., said on a conference call that he was “quite pleased” with the efficacy and safety of MGL-3196 in HeFH, particularly as the data also provides additional reassurance about the role of MGL-3196 in NASH, as cardiovascular complications are a feature with fatty lipid disease.

He told analysts the company now has “multiple shots on goal” with the drug but wouldn’t be drawn yet on the preferred route to market given that Madrigal now has positive trials in both NASH and HeFH. He did note that the profile also suggests that MGL-3196 could have a role to play more broadly in dyslipidemias.

HeFH is the most common dominantly inherited disease, present in up to 1 in 200 people, but developing the drug for other elevated cholesterol disorders could open the door to a much bigger market. The slow uptake of newer cholesterol-lowering drugs such as Amgen’s Repatha and Sanofi’s Praluent—both injectable PCSK9 inhibitors—has shown that improving lipid profiles isn’t however a guarantee of commercial success.

Friedman noted that it may be more palatable for patients and their doctors to add one daily pill to an existing oral regimen than introducing an injectable drug.